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Background Thyroid dysfunction in pregnancy is associated with adverse offspring outcomes and recent birth-cohort studies suggest that even mild degrees of thyroid dysfunction may be linked with a range of late cognitive and behavioural effects in childhood and adolescence. Sources of data This review summarizes recent literature of observational studies and critically appraises randomized controlled trials (RCTs) of antenatal thyroid screening and Levothyroxine intervention. Areas of agreement Overt hypothyroidism and hyperthyroidism carry significant risks for unfavourable offspring outcomes and should be appropriately corrected in pregnancy. Areas of controversy The significance of subclinical hypothyroidism and hypothyroxinaemia is still unclear. Meta-analyses of birth-cohort studies show associations of maternal subclinical hypothyroidism and hypothyroxinaemia with intellectual deficits, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders, while hyperthyroidism and high-normal FT4 were linked with ADHD. RCTs have shown no benefits of screening on neurodevelopmental outcomes although Levothyroxine could have been initiated too late in pregnancy in these trials. Growing points A small number of studies have shown inconsistent associations of maternal thyroid dysfunction with offspring cardiometabolic indices including blood pressure and body weight. Correction of maternal thyroid dysfunction was, however, associated with favourable long-term metabolic profiles in mothers, including lipid profiles, fat mass and body mass index. Antenatal thyroid screening may therefore present opportunities for optimizing a wider range of outcomes than envisaged. Areas for developing research Future trials with early antenatal thyroid screening and intervention are necessary to clarify the impact of screening on late offspring and maternal effects.

Objective\ud To determine the characteristics and outcomes of pregnancy in women with Turner Syndrome\ud \ud Design\ud Retrospective 20-year cohort study (2000-2020)\ud \ud Setting\ud 16 tertiary referral maternity units in the UK\ud \ud Population or Sample\ud 81 women with Turner syndrome who became pregnant\ud \ud Methods\ud Retrospective chart analysis\ud \ud Main Outcome Measures\ud Mode of conception, pregnancy outcomes\ud \ud Results\ud We obtained data on 127 pregnancies in 81 women with a Turner phenotype. All non-spontaneous pregnancies (54/127 (42.5%)) were by egg donation. Only 9/31 (29%) of pregnancies in women with karyotype 45,X were spontaneous, compared with 53/66 (80.3%) with mosaic karyotype 45,X/46,XX (p

Objective Poorly controlled salt-wasting (SW) congenital adrenal hyperplasia (CAH) patients often require high 9α-fluorocortisol doses as they show high levels of 17-hydroxyprogesterone (17OHP), which is a mineralocorticoid (MC)-receptor antagonist. Design We investigated the renin–angiotensin–aldosterone system in patients with SW-CAH receiving twice daily modified-release hydrocortisone (MR-HC, Efmody) compared with standard glucocorticoid (GC) therapy. Methods Data were analyzed from the 6-month, phase 3 study of MR-HC (n = 42) versus standard GC therapy (n = 41). MC replacement therapy remained unchanged throughout the study. Blood pressure, serum potassium, serum sodium, plasma renin activity (PRA), and serum 17OHP and androstenedione concentrations were analyzed at baseline, 4, 12, and 24 weeks. Results The median serum 17OHP in the morning was significantly lower on MR-HC compared with standard GC at 24 weeks (2.5 nmol L–1 (IQR 8.3) versus 10.5 nmol L–1 (IQR 55.2), P = .001). PRA decreased significantly from baseline to 24 weeks in patients on MR-HC (0.83 ng L–1 s–1 (IQR 1.0) to 0.48 ng L–1 s–1 (IQR 0.61), P = .012) but not in patients on standard GC (0.53 ng L–1 s–1 (IQR 0.66) to 0.52 ng L–1 s–1 (IQR 0.78), P = .613). Serum sodium concentrations increased from baseline to 24 weeks in patients on MR-HC (138.8 ± 1.9 mmol L–1 to 139.3 ± 1.8 mmol L–1, P = .047), but remained unchanged on standard GC (139.8 ± 1.6 mmol L–1 to 139.3 ± 1.9 mmol L–1, P = .135). No significant changes were seen in systolic and diastolic blood pressure and serum potassium levels. Conclusion 6 months of MR-HC therapy decreased PRA and increased sodium levels indicating a greater agonist action of the 9α-fluorocortisol dose, which may be due to the decreased levels of the MC-receptor antagonist 17OHP.

Identifying emotions correctly is essential for successful social interaction. There is therefore a keen interest in designing therapeutic interventions to improve emotion recognition in individuals who struggle with social interaction. The neuropeptide oxytocin has been proposed as a potential physiological intervention due to its important role in emotion recognition and other aspects of social cognition. However, there are a number of caveats to consider with the current form of intranasal oxytocin commonly used in the literature. Psychological interventions, on the other hand, do not carry the same caveats, and there is, therefore, a need to understand how intranasal oxytocin administration compares to psychological interventions designed to target the same psychological phenomena; and whether a combined intervention approach may provide additive benefits. Here we present a pilot, proof-of-concept study in healthy volunteers comparing the effect of intranasal oxytocin against a validated emotion training programme, finding that the psychological intervention, and not intranasal oxytocin, improved emotion recognition specifically for angry expressions. We discuss the theoretical implications of the research for future clinical trials. This article is part of the theme issue ‘Interplays between oxytocin and other neuromodulators in shaping complex social behaviours’.

Background Thyroid hormone is essential for optimal human neurodevelopment and may modify the risk of attention-deficit/hyperactivity disorder (ADHD). However, the brain structures involved are unknown and it is unclear if the adult brain is also susceptible to changes in thyroid status. Methods We used International Classification of Disease-10 codes, polygenic thyroid scores at different thresholds of association with thyroid traits (PT-values), and image-derived phenotypes in UK Biobank (n = 18 825) to investigate the effects of a recorded diagnosis of thyroid disease and genetic risk for thyroid status on cerebellar and subcortical gray matter volume. Regional genetic pleiotropy between thyroid status and ADHD was explored using the GWAS-pairwise method. Results A recorded diagnosis of hypothyroidism (n = 419) was associated with significant reductions in total cerebellar and pallidum gray matter volumes (β [95% CI] = −0.14[−0.23, −0.06], P = 0.0005 and β [95%CI] = −0.12 [−0.20, −0.04], P = 0.0042, respectively), mediated in part by increases in body mass index. While we found no evidence for total cerebellar volume alterations with increased polygenic scores for any thyroid trait, opposing influences of increased polygenic scores for hypo- and hyperthyroidism were found in the pallidum (PT < 1e−3: β [95% CI] = −0.02 [−0.03, −0.01], P = 0.0003 and PT < 1e−7: β [95% CI] = 0.02 [0.01, 0.03], P = 0.0003, respectively). Neither hypo- nor hyperthyroidism showed evidence of regional genetic pleiotropy with ADHD. Conclusions Thyroid status affects gray matter volume in adults, particularly at the level of the cerebellum and pallidum, with potential implications for the regulation of motor, cognitive, and affective function.

Background Prednisolone and prednisone have a longer plasma elimination half-life after oral administration than hydrocortisone: 2.1 to 3.5 vs ∼1.5hrs1,2. For this reason, prednis(ol)one has been used in Congenital Adrenal Hyperplasia (CAH) by giving a dose in the evening to try to prevent the overnight rise in adrenal androgens. Modified-release hydrocortisone (MRHC) capsules, (Efmody, Diurnal Ltd, Cardiff UK), replicate the cortisol diurnal rhythm and improve the control of CAH compared to standard glucocorticoid therapy3. This post-hoc sub-analysis examines CAH control in MRHC treated patients switched from prednis(ol)one. Methods We reviewed the data of all patients taking prednis(ol)one in the randomised study of standard treatment versus MRHC3: 39 classic CAH patients on prednis(ol)one (alone or combined with hydrocortisone) (36 prednisolone; 3 prednisone) were randomised either to continue prednis(ol)one or switched to MRHC at the same hydrocortisone dose equivalent (HDE=prednisolone dose x5). Patients were assessed after 4 weeks following which blinded dose titration according to 17OHP and A4 control was performed to bring 17OHP into the optimal range ( Results Median baseline dose (HDE) was 30mg (n=39), androgen control was 56%. In patients randomised to MRHC (n=18), 39% were controlled at baseline and 94% at 4 weeks without dose adjustment. At 24 weeks, after androgen-control guided titration, the HDE dose in the prednis(ol)one group was 34mg, and in the MRHC group 27.5mg, with control being 71% and 94%, respectively. Percentage inhibition of 9am 17OHP from the levels at baseline to that at 24 weeks in the prednis(ol)one group was 32% and in the MRHC group 91%. In this study period there were no adrenal crises in the MRHC group and one in the prednis(ol)one group. MRHC-treated patients in the extension study were further titrated according to clinician assessment, at interim analysis the median MRHC dose was 20mg (median reduction 10mg) and 82% of patients were controlled at 18 months (n=28). In the ongoing extension study of all patients on MRHC (221 patient years), there were 12 adrenal crises in 5 patients (5.4/100 patient years). Conclusions Control of CAH is better on MRHC than prednisolone: 94% vs 39%; and the dose of MRHC can be down titrated to an adrenal replacement dose whilst maintaining control in the majority (82%) of patients. References 1. Pickup ME. Clin Pharmacokinet 1979 4 111-128; 2. Toothaker RD. J Pharm Sci 1982 71 573-576; 3. Merke DP. JCEM 2021 106 e2063-e2077. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

As elite athletes demonstrate through the Olympic motto ‘Citius, Altius, Fortius- Communiter’, new performance records are driven forward by favourable skeletal muscle bioenergetics, cardiorespiratory, and endocrine system adaptations. At a recreational level, regular physical activity is an effective nonpharmacological therapy in the treatment of many endocrine conditions. However, the impact of physical exercise on endocrine function and how best to incorporate exercise therapy into clinical care are not well understood. Beyond the pursuit of an Olympic medal, elite athletes may therefore serve as role models for showcasing how exercise can help in the management of endocrine disorders and improve metabolic dysfunction. This review summarizes research evidence for clinicians who wish to understand endocrine changes in athletes who already perform high levels of activity as well as to encourage patients to exercise more safely. Herein, we detail the upper limits of athleticism to showcase the adaptability of human endocrine-metabolic-physiological systems. Then, we describe the growing research base that advocates the importance of understanding maladaptation to physical training and nutrition in males and females; especially the young. Finally, we explore the impact of physical activity in improving some endocrine disorders with guidance on how lessons can be taken from athletes training and incorporated into strategies to move more people more often.

Individuals who experience social and emotional difficulties struggle to maintain successful social relationships and incur an increased risk of developing mood disorders. These, in turn, have a significant impact on psychological and physical wellbeing. A small number of medical studies suggest that patients with adult-onset craniopharyngioma (AoC) report poorer quality of life, however, no in-depth psychological research has been carried out. The present study aimed to capture a rich understanding of whether patients with AoC experience a psychological impact from their diagnosis and whether psychological factors may contribute to a poorer quality of life. Both patients with AoC and clinicians with experience of working with patients with AoC were invited to take part in a semi-structured interview. Participants were recruited from three geographically disperse National Health Service (NHS) units across the United Kingdom (UK). Eight patients and 10 clinicians took part in the study. Interviews were analysed using inductive thematic analysis. Three themes, with multiple subthemes, were identified: 1) Patients experience psychological impacts of AoC; 2) Patients also experience common physical symptoms; and 3) Further research into the psychological impacts of AoC is necessary and interesting. Patients and clinicians recognised significant psychological impact as a result of AoC, and these impacts contributed to overall poorer quality of life. Crucially, both parties also felt that further research into psychological impact of AoC was both interesting and useful.

Summary Excess cortisol is associated with hypertrophy and redistribution of adipose tissue leading to central obesity which is classically seen in Cushing’s syndrome. Abnormal accumulation of fatty tissue in the spinal canal is most commonly associated with chronic steroid therapy and rarely reported with endogenous Cushing’s syndrome. Herein, we describe a case of spinal epidural lipomatosis (SEL) associated with Cushing’s disease. A 17-year-old man was referred with lower limb weakness, weight gain, multiple stretch marks, back pain and loss of height. He had clinical and biochemical features of Cushing’s syndrome. MRI and Inferior Petrosal Sinus Sampling (IPSS) confirmed a pituitary adenoma as the source. On day 1 post trans-sphenoidal adenectomy he developed spastic paraparesis with a sensory deficit to the level of T5. MRI spine showed increased fat deposition in the spinal canal from T2 to T9 consistent with a diagnosis of SEL. He was managed conservatively and made a good recovery following restoration of eucortisolism and a period of rehabilitation. Learning points: SEL is a serious complication of glucocorticoid excess and should be considered in any patient presenting with new lower limb neurological symptoms associated with hypercortisolism. It is important to distinguish symptomatic SEL from cortisol-induced proximal myopathy by good history and clinical examination. MRI of the spine is the gold standard investigation for making a diagnosis of SEL. Restoration of eucortisolism can lead to resolution of fat accumulation and good neurological outcome.

Objective: Polycystic ovary syndrome (PCOS) is associated with metabolic risk. Complement proteins regulate inflammation and lipid clearance but their role in PCOS‐associated metabolic risk is unclear. We sought to establish whether the complement system is activated in PCOS in the fasting and postprandial state.\ud \ud Design: Case‐control study.\ud \ud Patients: Fasting complement levels were measured in 84 women with PCOS and 95 healthy controls. Complement activation post‐oral fat tolerance test (OFTT) was compared in 40 additional subjects (20 PCOS, 20 controls).\ud \ud Measurements: Activation pathway (C3, C4, C3a(desArg), factor B, factor H, properdin, Factor D) and terminal pathway (C5, C5a, terminal complement complex [TCC]) proteins were measured by commercial or in‐house assays.\ud \ud Results: Fasting C3, C3a(desArg) and TCC concentrations were increased in insulin‐resistant (adjusted differences: C3 0.13 g/L [95%CI 0‐0.25]; C3a(desArg) 319.2 ng/mL [19.5‐619]; TCC 0.66 μg/mL [0.04‐1.28]) but not in insulin‐sensitive women with PCOS. C3 and factor H levels increased with obesity. Post‐OFTT, C3 and C4 levels increased to a similar extent in PCOS subjects and controls, whist factor H levels increased more in women with PCOS compared to controls (adjusted differences (area under the curve): 12 167 μg min/mL [4942‐19 392]), particularly in the presence of concomitant obesity.\ud \ud Conclusions: Activation and terminal complement pathway components are elevated in patients with PCOS, especially in the presence of insulin resistance and obesity.

Context and Objectives The Controlled Antenatal Thyroid Screening Study I (CATS-I) was a randomized controlled trial investigating the effects of levothyroxine therapy for suboptimal gestational thyroid function (SGTF), comparing outcomes in children of treated (SGTF-T) with untreated (SGTF-U) women during pregnancy. This follow-up study, CATS-II, reports the long-term effects on anthropometric, bone, and cardiometabolic outcomes in mothers and offspring and includes a group with normal gestational thyroid function (NGTF). Design & Participants 332 mothers (197 NGTF, 56 SGTF-U, 79 SGTF-T) aged 41.2±5.3 years (mean±SD) and 326 paired children assessed 9.3±1.0 years after birth for (i) body mass index (BMI); (ii) lean, fat, and bone mass by dual-energy X-ray absorptiometry; (iii) blood pressure, augmentation index, and aortic pulse-wave-velocity; and (iv) thyroid function, lipids, insulin, and adiponectin. The difference between group means was compared using linear regression. Results Offspring’s measurements were similar between groups. Although maternal BMI was similar between groups at CATS-I, after 9 years (at CATS-II) SGTF-U mothers showed higher BMI (median [interquartile ratio] 28.3 [24.6-32.6] kg/m2) compared with NGTF (25.8 [22.9-30.0] kg/m2; P = 0.029), driven by fat mass increase. At CATS-II SGTF-U mothers also had higher thyroid-stimulating hormone (TSH) values (2.45 [1.43-3.50] mU/L) than NGTF (1.54 [1.12-2.07] mU/L; P = 0.015), since 64% had never received levothyroxine. At CATS-II, SGTF-T mothers had BMI (25.8 [23.1-29.8] kg/m2, P = 0.672) and TSH (1.68 [0.89-2.96] mU/L; P = 0.474) values similar to NGTF mothers. Conclusions Levothyroxine supplementation of women with SGTF did not affect long-term offspring anthropometric, bone, and cardiometabolic measurements. However, absence of treatment was associated with sustained long-term increase in BMI and fat mass in women with SGTF.

Background Phaeochromocytomas (PCC) and paragangliomas (PGL) are rare neuroendocrine tumours of chromaffin cells that secrete catecholamines. The understanding of their aetiology and management is evolving. This study aimed to examine aspects in the management of PCC and PGL over the last decade. Methods Patients undergoing surgery for PCC/PGL over an eleven-year period were studied using a prospectively maintained database and electronic hospital clinical portal. Appropriate statistics were then employed. Results Sixty-nine patients underwent surgery (35 female, median age 52 years (12–82) to treat 57 PCC (inc. 2 bilateral) and 14 PGLs (inc. 2 recurrences). Although PCC and PGL patients were matched for gender and tumour-size, those with PGL were younger (median 40 (12–75) versus 54 (23–82), p = 0.044). PGL patients were also more likely to have a genetic abnormality identified (58.3% versus 16.1%, p = 0.002) and to have a malignant tumour (38.5% vs 6.8%, p = 0.002). Peri-operative blockade regimes were similar, but PGLs more frequently had an open procedure (42.9% vs 5.3% p Conclusions PGLs represent an even rarer subset of an already rare tumour-type. Access to multi-disciplinary specialists and appropriate decision-making are critical. High incidence of inherited disease, increased malignancy and recurrence rates along with the increased operative complexity favour greater use of open surgery and specialised follow-up to ascertain recurrence, as well as access to high quality genetic counselling services.

Objective\ud Thyroid status in the months following radioiodine treatment for Graves’ disease can be unstable.Our objective was to quantify frequency of abnormal thyroid function post-radioiodine and compare effectiveness of common management strategies.\ud \ud Design\ud Retrospective, multi-centre, observational study.\ud \ud Patients\ud Adult patients with Graves’ disease treated with radioiodine with 12 months’ follow-up.\ud \ud Measurements\ud Euthyroidism was defined as both serum thyrotropin (TSH) and free thyroxine (FT4) within their reference ranges or, when only one was available, it was within its reference range; hypothyroidism as TSH ≥ 10 mu/L, or subnormal FT4 regardless of TSH; hyperthyroidism as TSH below and FT4 above their reference ranges; dysthyroidism as the sum of hypo- and hyperthyroidism; subclinical hypothyroidism as normal FT4 and TSH between the upper limit of normal and

Context Depot-specific expansion of orbital adipose tissue (OAT) in Graves orbitopathy (GO; an autoimmune condition producing proptosis, visual impairment and reduced quality of life) is associated with fatty acid (FA)-uptake–driven adipogenesis in preadipocytes/fibroblasts (PFs). Objective This work sought a role for mitochondria in OAT adipogenesis in GO. Methods Confluent PFs from healthy OAT (OAT-H), OAT from GO (OAT-GO) and white adipose tissue in culture medium compared with culture medium containing a mixed hormonal cocktail as adipogenic medium (ADM), or culture-medium containing FA-supplementation, oleate:palmitate:linoleate (45:30:25%) with/without different concentration of mitochondrial biosubstrate adenosine 5′-diphosphate/guanosine 5′-diphosphate (ADP/GDP), AICAR (adenosine analogue), or inhibitor oligomycin-A for 17 days. Main outcome measures included oil-red-O staining and foci count of differentiated adipocytes for in vitro adipogenesis, flow cytometry, relative quantitative polymerase chain reaction, MTS-assay/106 cells, total cellular-ATP detection kit, and Seahorse-XFe96-Analyzer for mitochondria and oxidative-phosphorylation (OXPHOS)/glycolysis-ATP production analysis. Results During early adipogenesis before adipocyte formation (days 0, 4, and7), we observed OAT-specific cellular ATP production via mitochondrial OXPHOS in PFs both from OAT-H and OAT-GO, and substantially disrupted OXPHOS-ATP/glycolysis-ATP production in PFs from OAT-GO, for example, a 40% reduction in OXPHOS-ATP and trend-increased glycolysis-ATP production on days 4 and 7 compared with day 0, which contrasted with the stable levels in OAT-H. FA supplementation in culture-medium triggered adipogenesis in PFs both from OAT-H and OAT-GO, which was substantially enhanced by 1-mM GDP reaching 7% to 18% of ADM adipogenesis. The FA-uptake–driven adipogenesis was diminished by oligomycin-A but unaffected by treatment with ADP or AICAR. Furthermore, we observed a significant positive correlation between FA-uptake–driven adipogenesis by GDP and the ratios of OXPHOS-ATP/glycolysis-ATP through adipogenesis of PFs from OAT-GO. Conclusion Our study confirmed that FA uptake can drive OAT adipogenesis and revealed a fundamental role for mitochondria-OXPHOS in GO development, which provides potential for therapeutic interventions.

Introduction: Polycystic Ovary syndrome (PCOS) is a metabolic disorder associated with increased cardiovascular disease risk. Exercise is an effective treatment strategy to manage symptoms and reduce long-term health risk. High-intensity interval training (HIIT) has been suggested as a more efficient exercise mode in PCOS; however, it is not clear whether HIIT is superior to moderate intensity steady state exercise (MISS). Methods: We synthesized available data through a systematic review and meta-analysis to compare the effectiveness of isolated HIIT and MISS exercise interventions. Our primary outcome measures were cardiorespiratory fitness and insulin resistance, measured using V˙O2max and HOMA-IR respectively. Results: A total of 16 studies were included. Moderate-quality evidence from 16 studies identified significant improvements in V˙O2max following MISS (Δ = 1.081 ml/kg/min, p < 0.001, n = 194), but not HIIT (Δ = 0.641 ml/kg/min, p = 0.128, n = 28). Neither HIIT nor MISS improved HOMA-IR [(Δ = −0.257, p = 0.374, n = 60) and (Δ = −0.341, p = 0.078, n = 159), respectively]. Discussion: A significant improvement in V˙O2max was evident following MISS, but not HIIT exercise in women with PCOS. This contrasts with previous literature in healthy and clinical cohorts that report superior benefits of HIIT. Therefore, based on available moderate-quality evidence, HIIT exercise does not provide superior outcomes in V˙O2max compared with MISS, although larger high-quality interventions are needed to fully address this. Additional dietary/pharmacological interventions may be required in conjunction with exercise to improve insulin sensitivity.

Background\udExtracellular vesicles (EVs) derived from endothelial cells are elevated in cardiovascular disease and promote inflammation and coagulation. Hypoxia is often a key feature and is itself a potent stimulator of increased EV production. Inorganic nitrite (NO2−) has beneficial and protective effects that are enhanced in hypoxia.\ud\udObjectives\udInvestigate the impact of hypoxia on the functional capacity of EV derived from endothelial cells under hypoxia, and assess whether pre-treatment of endothelial cells with NO2− can alter EV function.\ud\udMethods\udDifferential ultracentrifugation was used to isolate EV from the cultured endothelial cell line HECV (CEV), and from primary human umbilical cord derived endothelial cells (PEV), with time-resolved fluorescence used to assess EV protein composition. Clot formation was induced by thrombin and calcium in two assays; using an Alexa Fluor 594 human fibrinogen conjugate assay and standard turbidometry. Platelet aggregation was determined using multiple electrode aggregometry. Scanning electron microscopy was used to visualise fibrin clots.\ud\udResults\udHypoxia exposure (1% O2) significantly increased CEV production in comparison to normoxia (21% O2) (1825 ± 72 EVs/cell vs 117 ± 9 EVs/cell, p < 0.001, respectively) but had no effect on CEV mean size (221 ± 6 nm vs 203 ± 4 nm, p > 0.05). Hypoxia-derived PEVs contained significantly more tissue factor than normoxia-derived EVs (Relative Fluorescence Units (RFU) = 7666 ± 1698 vs 5958 ± 1644, p < 0.001, respectively) and less tissue factor pathway inhibitor (RFU = 9799 ± 2353 vs 19723 ± 2698, p < 0.05). Hypoxia significantly increased CEV induced fibrin polymer formation compared to normoxia (% area = 46.98 ± 0.97 vs 36.36 ± 0.72, p < 0.05). Pre-treatment of endothelial cells with NO2− in hypoxia abrogated this effect (% area = 15.70 ± 1.99, p < 0.001). Hypoxia derived CEV non-significantly increased the maximum clot formed, shortened time to max clot, and increased time to clot lysis by turbidometry. ADP-mediated platelet aggregation was significantly elevated with PEV derived from hypoxia compared to normoxia (888.0 ± 32.2 AU*min vs 671.5.2 ± 28.3 AU*min, p < 0.01). This was abrogated by pre-treatment of hypoxic endothelial cells with NO2− (716.5 ± 744.3 AU*min, p < 0.001).\ud\udConclusions\udHypoxia-derived PEVs and CEVs exhibit increased procoagulant activity compared to normoxia-derived EVs, which we confirm to be mediated by an imbalance of TF/TFPI. Pre-treatment of endothelial cells with NO2− reduces the pro-coagulant activity of EVs via a mechanism that is Hypoxia-inducible factor 1 (HIF-1) dependent, but independent of TF/TFPI.

Context The effects of polycystic ovary syndrome (PCOS) on cardiovascular morbidity and mortality are unclear. Objective This work aims to establish the relative risk of myocardial infarction (MI), stroke, angina, revascularization, and cardiovascular mortality for women with PCOS. Methods Data were extracted from the Clinical Practice Research Datalink Aurum database. Patients with PCOS were matched to controls (1:1) by age, body mass index (BMI) category, and primary care practice. The primary outcome was the time to major adverse cardiovascular event (MACE); a composite end point incorporating MI, stroke, angina, revascularization and cardiovascular mortality. Secondary outcomes were the individual MACE end points. Results Of 219 034 individuals with a diagnosis of PCOS, 174 660 (79.7%) met the eligibility criteria and were matched. Crude rates of the composite end point, MI, stroke, angina, revascularization, and cardiovascular mortality were respectively 82.7, 22.7, 27.4, 32.8, 10.5, and 6.97 per 100 000 patient-years for cases, and 64.3, 15.9, 25.7, 19.8, 7.13, and 7.75 per 100 000 patient-years for controls. In adjusted Cox proportional hazard models (CPHMs), the hazard ratios (HRs) were 1.26 (95% CI, 1.13-1.41), 1.38 (95% CI, 1.11-1.72), 1.60 (95% CI, 1.32-1.94), and 1.50 (95% CI, 1.08-2.07) for the composite outcome, MI, angina, and revascularization, respectively. In a time-dependent CPHM, weight gain (HR 1.01; 1.00-1.01), prior type 2 diabetes mellitus (T2DM) (HR 2.40; 1.76-3.30), and social deprivation (HR 1.53; 1.11-2.11) increased risk of progression to the composite end point. Conclusion The risk of incident MI, angina, and revascularization is increased in young women with PCOS. Weight and T2DM are potentially modifiable risk factors amenable to intervention.

Introduction Individuals who experience social and emotional difficulties struggle to maintain successful social relationships and incur an increased risk of developing mood disorders. These, in turn, have been found to have a significant impact on both psychological and physical wellbeing. A small number of medical studies suggest that patients with adult-onset craniopharyngioma (AoC) report a poorer quality of life, however, no psychological research has been carried out. The present study aimed to capture, for the first time, a detailed description of AoC patients’ lives outside the clinic. Specifically, whether they experience a psychological impact from their diagnosis and whether psychological factors may contribute to a poorer quality of life. Methods Both patients with AoC and clinicians with experience of working with patients with AoC were invited to take part in a semi-structured interview. Clinicians were recruited with the view to providing an alternative viewpoint and the possibility to assess potential (mis)matches in perceptions of AoC patients’ social strengths and difficulties. Participants were recruited from three geographically disperse NHS units across the UK. Eight patients and 11 clinicians took part in the study. Interviews were analysed using inductive thematic analysis wherebycodes are identified which represent statements centring on a similar topic that are endorsed by multiple participants. Codes that are frequently used are compiled into larger themes, reflecting broader topics. Results The central theme of 'symptoms’ was consistent across patients and clinicians and consisted of three sub-themes: physical symptoms, psychological symptoms, and the tendency for patients to hide symptoms. Both cohorts stated that weight gain and fatigue were the most common physical symptoms, but these were also closely related to psychological symptoms, such as changing lifestyle patterns and a shrinking social network. Crucially, both cohorts stated that low mood, anxiety, and low self-esteem were common and significant experiences. Both cohorts discussed instances of specific mental health disorders. Conversely, some patients tried to hide symptoms with diminishing or contradictory statements or acknowledged that others had encouraged them to seek help, a theme that was also found with clinicians. In addition to these similarities there were also important differences in perceptions. Firstly, while clinicians believed they were open to or actively discussed a patient's psychological wellbeing during consultations, many patients felt they had never been asked about this. Secondly, while some clinicians were very clear on the extreme negative impact of the condition, patients also described more subtle social impacts. Finally, clinicians felt a sense of frustration regarding poor, unspecialised, under resourced psychological support, a feeling that was not common among patients. Conclusion In conclusion, both patients and clinicians recognised significant psychological impact as a result of AoC. Further research is planned to quantitively assess the topics raised in the present study. Presentation: No date and time listed

Extracellular vesicles (EVs) are nanometre-sized vesicles released from most cells, including adipocytes. Relatively little is known about adipocyte-derived EVs (ADEVs) in comparison to other EV subtypes, though interest in ADEVs as potential paracrine and endocrine communicators of adipose tissue in obesity is building. Current evidence indicates that ADEVs contribute to the development of adipose tissue dysfunction; a key feature of obese adipose tissue that it is associated with obesity-related comorbidities including cardiovascular disease (CVD). This review summarises our current knowledge of ADEVs in the development of adipose tissue dysfunction and the potential of ADEVs to disrupt redox signalling and exert vascular effects that may exacerbate CVD in obesity.

Introduction: Polycystic Ovary syndrome (PCOS) is a metabolic disorder associated with increased cardiovascular disease risk. Exercise is an effective treatment strategy to manage symptoms and reduce long-term health risk. High-intensity interval training (HIIT) has been suggested as a more efficient exercise mode in PCOS; however, it is not clear whether HIIT is superior to moderate intensity steady state exercise (MISS).Methods: We synthesized available data through a systematic review and meta-analysis to compare the effectiveness of isolated HIIT and MISS exercise interventions. Our primary outcome measures were cardiorespiratory fitness and insulin resistance, measured using V˙O2max and HOMA-IR respectively.Results: A total of 16 studies were included. Moderate-quality evidence from 16 studies identified significant improvements in V˙O2max following MISS (Δ = 1.081 ml/kg/min, p < 0.001, n = 194), but not HIIT (Δ = 0.641 ml/kg/min, p = 0.128, n = 28). Neither HIIT nor MISS improved HOMA-IR [(Δ = −0.257, p = 0.374, n = 60) and (Δ = −0.341, p = 0.078, n = 159), respectively].Discussion: A significant improvement in V˙O2max was evident following MISS, but not HIIT exercise in women with PCOS. This contrasts with previous literature in healthy and clinical cohorts that report superior benefits of HIIT. Therefore, based on available moderate-quality evidence, HIIT exercise does not provide superior outcomes in V˙O2max compared with MISS, although larger high-quality interventions are needed to fully address this. Additional dietary/pharmacological interventions may be required in conjunction with exercise to improve insulin sensitivity.

The clinical course of pituitary adenoma can be highly variable. Aggressive pituitary tumours may require multimodal therapy with multiple operations. Even standard pituitary adenomas exhibit relatively high long-term recurrence rates and delayed intervention is often required. The indications for revision surgery in the endoscopic era are expanding for both functioning and nonfunctioning tumours, including access to the cavernous sinus and intracranial compartments. Although revision surgery can be challenging, it has been demonstrated to be both safe and effective. The question of the use of early radiotherapy in pituitary adenoma remains controversial. Our increasing understanding of pituitary tumour biology facilitates individualized treatment and surveillance protocols, with early intervention in high-risk adenoma subtypes. In this review, we discuss the treatment options for recurring pituitary tumours and focus on the role of revision surgery.

Context & Objectives The Controlled Antenatal Thyroid Screening (CATS) study was the first randomized controlled trial to investigate effects of treating suboptimal gestational thyroid function (SGTF) on child cognition. Since observational studies indicated that SGTF may also increase symptoms of autism and attention-deficit/hyperactivity disorder (ADHD), the CATS cohort was used to investigate whether treatment of mothers affected their children’s behavior. Design & Participants Mothers (N = 475) completed 3 questionnaires: the Strengths and Difficulties Questionnaire (SDQ), the Child ADHD Questionnaire, and the Social Communication Questionnaire (SCQ, used as a screen for autism spectrum disorder [ASD]), about their children (mean age 9.5 years). Group comparisons of total scores, numbers of children above clinical thresholds, and association between high maternal free thyroxine (FT4) (> 97.5th percentile of the UK cohort, “overtreated”) and child neurodevelopment were reported. Results There were no differences in total scores between normal gestational thyroid function (GTF) (n = 246), treated (n = 125), and untreated (n = 104) SGTF groups. More children of treated mothers scored above clinical thresholds, particularly the overtreated. Scores were above thresholds in SDQ conduct (22% vs 7%), SCQ total scores (7% vs 1%), and ADHD hyperactivity (17% vs 5%) when comparing overtreated (n = 40) and untreated (N = 100), respectively. We identified significantly higher mean scores for SDQ conduct (adjusted mean difference [AMD] 0.74; 95% confidence interval [CI], 0.021-1.431; P = 0.040, effect size 0.018) and ADHD hyperactivity (AMD 1.60, 95% CI, 0.361-2.633; P = 0.003, effect size 0.028) comparing overtreated with normal-GTF children. Conclusions There was no overall association between SGTF and offspring ADHD, ASD, or behavior questionnaire scores. However, children of “overtreated” mothers displayed significantly more ADHD symptoms and behavioral difficulties than those of normal-GTF mothers. Thyroxine supplementation during pregnancy requires monitoring to avoid overtreatment.

Context Polycystic ovary syndrome (PCOS) is associated with increased sympathetic nervous system activation, but the cerebral pathways involved are unclear. Objective To compare cerebral [blood oxygen level–dependent (BOLD) functional MRI], pressor [blood pressure (BP), heart rate (HR], and muscle sympathetic nerve activity (MSNA) responses to isometric forearm contraction (IFC) in women with PCOS and matched control subjects. Design Case-control study. Setting Referral center. Participants Patients with PCOS (n = 20; mean ± SD data: age, 29.8 ± 4.8 years; body mass index (BMI), 26.1 ± 4.9 kg/ m2) and 20 age- and BMI-matched control subjects (age, 29.7 ± 5.0 years; BMI, 26.1 ± 4.8 kg/ m2). Main outcome measures BP, HR, catecholamine, and MSNA responses to 30% IFC. BOLD signal change was modeled for BP response to 30% IFC. Results Although HR and BP increased to a similar extent in both groups after IFC, MSNA burst frequency increased by 68% in the PCOS group compared with 11.9% in control subjects (n = 7 in both groups; P = 0.002). Brain activation indexed by the BOLD signal in response to IFC was significantly greater in the PCOS group (n = 15) compared with controls (n = 15) in the right orbitofrontal cortex (P < 0.0001). Adjustment for insulin sensitivity, but not hyperandrogenism, abolished these between-group differences. Conclusion Our study confirms enhanced sympathoexcitation in women with PCOS and demonstrates increased regional brain activation in response to IFC. The right orbitofrontal cortex BOLD signal change in women with PCOS is associated with insulin sensitivity. Additional studies are warranted to clarify whether this may offer a novel target for cardiovascular risk reduction.

Thyroid stimulating antibodies (TSAB) cause Graves’ disease and contribute to Graves’ Orbitopathy (GO) pathogenesis. We hypothesise that the presence of TSH binding proteins (truncated TSHR variants (TSHRv)) and/or nonclassical ligands such as thyrostimulin (α2β5) might provide a mechanism to protect against or exacerbate GO. We analysed primary human orbital preadipocyte-fibroblasts (OF) from GO patients and people free of GO (non-GO). Transcript (QPCR) and protein (western blot) expression levels of TSHRv were measured through an adipogenesis differentiation process. Cyclic-AMP production by TSHR activation was studied using luciferase-reporter and RIA assays. After differentiation, TSHRv levels in OF from GO were significantly higher than non-GO (p = 0.039), and confirmed in ex vivo analysis of orbital adipose samples. TSHRv western blot revealed a positive signal at 46 kDa in cell lysates and culture media (CM) from non-GO and GO-OF. Cyclic-AMP decreased from basal levels when OF were stimulated with TSH or Monoclonal TSAB (M22) before differentiation protocol, but increased in differentiated cells, and was inversely correlated with the TSHRv:TSHR ratio (Spearman correlation: TSH r = −0.55, p = 0.23, M22 r = 0.87, p = 0.03). In the bioassay, TSH/M22 induced luciferase-light was lower in CM from differentiated GO-OF than non-GO, suggesting that secreted TSHRv had neutralised their effects. α2 transcripts were present but reduced during adipogenesis (p &lt, 0.005) with no difference observed between non-GO and GO. β5 transcripts were at the limit of detection. Our work demonstrated that TSHRv transcripts are expressed as protein, are more abundant in GO than non-GO OF and have the capacity to regulate signalling via the TSHR.

Context A lack of consensus remains about the relative importance of insulin-like growth factor-1 (IGF-1) and growth hormone (GH) in predicting adverse outcomes in patients with acromegaly. Objective To describe the differing association between IGF-1 and GH and major disease outcomes in acromegaly. Design Retrospective cohort study. Patients United Kingdom National Health Service patients with acromegaly who had an IGF-1 and/or a GH measurement recorded following diagnosis, prior to December 2019. Measurements A composite endpoint including all-cause mortality (ACM), type 2 diabetes (DM), major adverse cardiovascular events (MACE) or cancer was the primary outcome. These outcomes were also analysed individually. Follow-up period was capped at 5 years. Results A maximum of 417 cases and 332 cases were eligible for the IGF-1 and GH analyses, respectively, comprising 1041.5 and 938.9 years of follow-up. There was a direct association between increased IGF-1 concentration and adjusted event risk for the composite endpoint (hazard ratio [HR] = 1.2; 95% confidence interval [CI] = 1.02-1.5); in GH, the HR was 1.1 (1.0-1.2). For the individual endpoints in relation to IGF-1 level, the HRs were ACM (1.2; 0.93-1.5), MACE (1.2; 0.64-2.1), DM (1.53; 1.09-2.2) and cancer (1.3; 0.95-1.7). For GH, the HRs were ACM (1.1; 0.97-1.2), MACE (0.99; 0.73-1.3), DM (1.1; 0.99-1.2) and cancer (0.90; 0.66-1.2). Conclusions In this contemporary data set with extended follow-up, IGF-1 and GH concentrations showed an association with major adverse outcomes from acromegaly.